EP0884948B1 - Antiseptic compositions containing chlorobutanol and chlorhexidine - Google Patents

Antiseptic compositions containing chlorobutanol and chlorhexidine Download PDF

Info

Publication number
EP0884948B1
EP0884948B1 EP97907152A EP97907152A EP0884948B1 EP 0884948 B1 EP0884948 B1 EP 0884948B1 EP 97907152 A EP97907152 A EP 97907152A EP 97907152 A EP97907152 A EP 97907152A EP 0884948 B1 EP0884948 B1 EP 0884948B1
Authority
EP
European Patent Office
Prior art keywords
chlorhexidine
chlorobutanol
per
concentration
antiseptic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP97907152A
Other languages
German (de)
French (fr)
Other versions
EP0884948A1 (en
Inventor
Christian Mroz
Rolland Segonds
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pierre Fabre Medicament SA
Original Assignee
Pierre Fabre Medicament SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pierre Fabre Medicament SA filed Critical Pierre Fabre Medicament SA
Publication of EP0884948A1 publication Critical patent/EP0884948A1/en
Application granted granted Critical
Publication of EP0884948B1 publication Critical patent/EP0884948B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
    • A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
    • A01N47/44—Guanidine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/43—Guanidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005—Antimicrobial preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/02—Preparations for cleaning the hair

Definitions

  • the present invention relates to antiseptic compositions combining Chlorhexidine or one of its salts and Chlorobutanol in particular proportions leading to synergy in terms of antiseptic activity.
  • These may in particular be preparations topical pharmaceuticals, but also disinfection products including medical equipment.
  • Chlorhexidine is a local antiseptic widely used in topical application (wounds, ENT care, irrigations of internal cavities, etc.) or as a disinfectant. It can be combined with other substances antimicrobials such as alcohol or quaternary ammoniums. The minimum concentrations of chlorhexidine salts then approach 100 mg, or even 50 mg per 100 ml.
  • Chlorobutanol is mainly used as an analgesic. His bacteriostatic type antimicrobial properties also allow its use as a preservative for compositions pharmaceutical.
  • Chlorobutanol is used in pharmaceutical compositions at concentrations which are very variable (from 25 to 500 mg per 100 ml). It can be combined with real antiseptics, but only ELUDRIL SOLUTION® (Pierre Fabre Médicament) combines it with Chlorhexidine.
  • the formula marketed in France contains 100 mg per 100 ml of Chlorhexidine digluconate and 100 mg per 100 ml of Chlorobutanol hemihydrate. This solution is used diluted to half or a quarter and the activity antiseptic is attributed to Chlorhexidine. Only sedative activity is attributed to Chlorobutanol.
  • a variant marketed in the Kingdom Uni contains the same amount of Chlorhexidine, but 500 mg per 100 ml of Chlorobutanol hemihydrate. The properties observed for both components are the same and it is always a solution to be diluted.
  • the antiseptic composition based on a combination of anhydrous or hemihydrated Chlorobutanol with Chlorhexidine or one of its salts is characterized in that the Chlorobutanol is present at a minimum concentration of around 200 mg per 100 ml, Chlorhexidine or its salt is present at a concentration, expressed as Chlorhexidine base, from 0.28 mg to 14 mg for 100 ml, and the weight ratio between Chlorobutanol and Chlorhexidine expressed in free base is between 14 and 1800.
  • the Chlorobutanol is present at a concentration of around 500 mg for 100 ml.
  • Gram-negative bacteria seem to be the most germs sensitive. However, the contact time required to obtain the 5 log reduction is approximately one hour.
  • Chlorobutanol has antimicrobial activity which is compatible with its use at a concentration of 500 mg for 100 ml as a preservative in preparations pharmaceutical.
  • these antimicrobial properties up to this concentration and even over very long periods of application (at least 4 hours) are clearly insufficient to claim an activity antiseptic according to the terms of the French Pharmacopoeia.
  • the antimicrobial activity of Chlorhexidine was determined from the same way.
  • concentrations of chlorhexidine salts in preparations antiseptics can thus vary from 50 to 4000 mg per 100 ml depending on the use and presentation of these products (solutions for local application used for the preparation of surgical drapes or antiseptic damaged skin, gels, mouthwashes, mouthwashes for the treatment of oral diseases, etc.).
  • Chlorhexidine in the form of its salts was quantified by fixing the most important of these parameters.
  • the contact temperature 32 ° C
  • the contact time was set at a deliberately short value (5 min) because it is very discriminating; it is also related to the therapeutic use sought.
  • the tests were carried out in the absence of agents interfering with the action of Chlorhexidine. Under these precise conditions of contact, the minimum concentrations necessary to reduce the concentration of living microorganisms by 10 5 times have been established according to the definition of the French Pharmacopoeia (Table 3).
  • Chlorhexidine base are equivalent for each of the salts tested (digluconate and diacetate).
  • Minimum antiseptic concentrations of Chlorhexidine base (mg per 100 ml) for 5 min contact at 32 ° C P. aeruginosa A22 2.8 E coli ATCC 10536 1.4 S. aureus ATCC 9144 28 E. hirae ATCC 10541 280
  • Chlorhexidine therefore acts very quickly and at low concentration on a broad bacterial spectrum. Values vary from germ to another.
  • Chlorhexidine - Chlorobutanol allows to obtain an antiseptic power in 1 min equivalent (case of S. mutans), even higher (case of A. actinomycetemcomitans) than that obtained after 5 min. of contact with Chlorhexidine alone. This is particularly true in case the doses applied in Chlorhexidine are very low (less than 5.6 mg per 100 ml). Under the same conditions of contact Chlorobutanol alone has little or no activity. Indeed, in presence of 500 mg per 100 ml of Chlorobutanol, the logarithm of reduction in S. mutans populations is zero after 5 min of contact at 32 ° C ( Figure 2 attached) and 1.3 for A. actinomycetemcomitans ( Figure 3 attached).
  • the present invention demonstrates that the addition of Chlorobutanol in preparations based on Chlorhexidine or its salts can significantly increase the activity of this antiseptic. Potentiation results in a decrease in useful concentration of Chlorhexidine and / or a reduction in the time useful contact for its action. This potentialization is also expressed by the fact that, for a given concentration, the spectrum of activity of the Chlorhexidine is enlarged thanks to the increased sensitivity of germs to this antiseptic.
  • Chlorobutanol / Chlorhexidine base optimum weight is between 14 and 1800. This active base can be transposed to all forms galenical: liquid, pasty, or solid.
  • Example of antiseptic solution for 100 ml Chlorhexidine digluconate 0.5 to 25 mg Chlorobutanol hemihydrate 200 to 500 mg Perfume from 0.05 to 3 ml
  • Purified water qs 100 ml Mouthwash example for 100 ml: Chlorhexidine digluconate 0.5 to 25 mg Chlorobutanol hemihydrate 200 to 500 mg 95% ethyl alcohol from 1 to 30 ml
  • Example of antibacterial cream for 100 ml Chlorhexidine diacetate 0.35 to 17.5 mg Chlorobutanol hemihydrate 200 to 500 mg Thick Vaseline Oil from 1 to 20 g Emulsifying wax based on fatty alcohol from 1 to 20 g Antioxidant from 10 to 500 mg Purified water qs 100

Abstract

An antiseptic composition containing a combination of chlorobutanol and chlorhexidine or a salt thereof, wherein the chlorobutanol is at a concentration of at least around 0.2 % m/V, the chlorhexidine or salt thereof is at a concentration of 0.0005-0.01 % m/V, and the weight ratio of chlorobutanol to chlorhexidine or the salt thereof is of 8-1000.

Description

La présente invention concerne des compositions antiseptiques associant la Chlorhexidine ou l'un de ses sels et le Chlorobutanol dans des proportions particulières conduisant à une synergie sur le plan de l'activité antiseptique. Il peut s'agir en particulier de préparations pharmaceutiques topiques, mais également de produits de désinfection notamment du matériel médical.The present invention relates to antiseptic compositions combining Chlorhexidine or one of its salts and Chlorobutanol in particular proportions leading to synergy in terms of antiseptic activity. These may in particular be preparations topical pharmaceuticals, but also disinfection products including medical equipment.

La Chlorhexidine est un antiseptique local largement utilisé en application topique (plaies, soins ORL, irrigations des cavités internes, etc) ou comme désinfectant. Elle peut être associée à d'autres substances antimicrobiennes comme de l'alcool ou des ammoniums quaternaires. Les concentrations minimales en sels de Chlorhexidine avoisinnent alors 100 mg, voire 50 mg pour 100 ml.Chlorhexidine is a local antiseptic widely used in topical application (wounds, ENT care, irrigations of internal cavities, etc.) or as a disinfectant. It can be combined with other substances antimicrobials such as alcohol or quaternary ammoniums. The minimum concentrations of chlorhexidine salts then approach 100 mg, or even 50 mg per 100 ml.

Le Chlorobutanol est surtout employé comme analgésique. Ses propriétés antimicrobiennes de type bactériostatique permettent aussi son utilisation comme agent de conservation des compositions pharmaceutiques.Chlorobutanol is mainly used as an analgesic. His bacteriostatic type antimicrobial properties also allow its use as a preservative for compositions pharmaceutical.

Le Chlorobutanol est utilisé dans les compositions pharmaceutiques à des concentrations qui sont très variables (de 25 à 500 mg pour 100 ml). Il peut être associé à de véritables antiseptiques, mais seul ELUDRIL SOLUTION® (Pierre Fabre Médicament) l'associe à de la Chlorhexidine. La formule commercialisée en France contient 100 mg pour 100 ml de Digluconate de Chlorhexidine et 100 mg pour 100 ml de Chlorobutanol hémihydraté. Cette solution s'utilise diluée au demi ou au quart et l'activité antiseptique est attribuée à la Chlorhexidine. Seule une activité sédative est attribuée au Chlorobutanol. Une variante commercialisée au Royaume Uni contient la même quantité de Chlorhexidine, mais 500 mg pour 100 ml de Chlorobutanol hémihydraté. Les propriétés observées pour les deux composants sont les mêmes et il s'agit toujours d'une solution à diluer.Chlorobutanol is used in pharmaceutical compositions at concentrations which are very variable (from 25 to 500 mg per 100 ml). It can be combined with real antiseptics, but only ELUDRIL SOLUTION® (Pierre Fabre Médicament) combines it with Chlorhexidine. The formula marketed in France contains 100 mg per 100 ml of Chlorhexidine digluconate and 100 mg per 100 ml of Chlorobutanol hemihydrate. This solution is used diluted to half or a quarter and the activity antiseptic is attributed to Chlorhexidine. Only sedative activity is attributed to Chlorobutanol. A variant marketed in the Kingdom Uni contains the same amount of Chlorhexidine, but 500 mg per 100 ml of Chlorobutanol hemihydrate. The properties observed for both components are the same and it is always a solution to be diluted.

Or, de façon surprenante, il a été trouvé que l'association de Chlorhexidine ou de l'un des sels avec le Chlorobutanol, sous forme anhydre ou hémihydratée, lorsqu'elle était convenablement réalisée, permettait une potentialisation de l'activité antimicrobienne de ces deux principes. Cette potentialisation s'exerce aussi bien sur les bactéries gram - négatives que sur les bactéries gram positives. Elle permet dans certains cas de réduire mille fois la dose nécessaire en Chlorhexidine pour obtenir un résultat équivalent. Surprisingly, it has been found that the association of Chlorhexidine or one of the salts with Chlorobutanol, in the form anhydrous or hemihydrated, when properly performed, allowed a potentiation of the antimicrobial activity of these two principles. This potentiation is exerted as well on gram bacteria - negative than on gram positive bacteria. It allows in some case of reducing a thousand times the dose necessary in Chlorhexidine to obtain an equivalent result.

Conformément à la présente invention, la composition antiseptique à base d'une association de Chlorobutanol anhydre ou hémihydraté avec de la Chlorhexidine ou l'un de ses sels est caractérisée en ce que le Chlorobutanol est présent à une concentration minimale d'environ 200 mg pour 100 ml, la Chlorhexidine ou son sel est présent à une concentration, exprimée en Chlorhexidine base, de 0,28 mg à 14 mg pour 100 ml, et le rapport pondéral entre le Chlorobutanol et la Chlorhexidine exprimée en base libre est compris entre 14 et 1800.According to the present invention, the antiseptic composition based on a combination of anhydrous or hemihydrated Chlorobutanol with Chlorhexidine or one of its salts is characterized in that the Chlorobutanol is present at a minimum concentration of around 200 mg per 100 ml, Chlorhexidine or its salt is present at a concentration, expressed as Chlorhexidine base, from 0.28 mg to 14 mg for 100 ml, and the weight ratio between Chlorobutanol and Chlorhexidine expressed in free base is between 14 and 1800.

Selon une caractéristique avantageuse de la présente invention, le Chlorobutanol est présent à une concentration d'environ 500 mg pour 100 ml.According to an advantageous characteristic of the present invention, the Chlorobutanol is present at a concentration of around 500 mg for 100 ml.

On a tout d'abord déterminé l'activité antimicrobienne du Chlorobutanol en solution aqueuse à 500 mg pour 100 ml. Pour cela, deux méthodologies ont été utilisées :

  • La méthodologie proposée par la Pharmacopée Européenne IIème édition dans l'annexe VIII.14 et intitulée "Efficacité de la conservation antimicrobienne". Dans cet essai, des suspensions de germes sont maintenues en contact avec le produit à évaluer jusqu'à 28 jours à 20-25°C. Le nombre de cellules survivant à ce contact est suivi en fonction de la durée de celui-ci. L'efficacité du pouvoir de conservation est exprimée en logarithme de réduction (logR) des populations de germes-test. Les souches à essayer sont stipulées par la Pharmacopée Européenne. Ce type d'essai réalisé sur le Chlorobutanol en solution aqueuse de 500 mg pour 100 ml a conduit aux résultats reportés dans le tableau 1 ci-après. Réduction logarithmique (LOG R) des populations microbiennes en fonction du temps de contact avec une solution aqueuse à 500 mg pour 100 ml de Chlorobutanol Souches test Temps de contact 48h 7j 14j 28j Pseudomonas acruginosa ATCC 9027 >4,4 >4,4 >4,4 >4,4 Escherichia coli ATCC 8739 >4,3 >4,3 >4,3 >4,3 Staphylococcus aureus ATCC 6538 >4,1 >4,1 >4,1 >4,1 Candida albicans ATCC 10231 >4 >4 >4 >4 Aspergillus niger ATCC 16404 0,4 1,8 2,4 2,6
  • La méthodologie décrite par la Pharmacopée Française Xème édition dans la monographie "Antiseptica" de Janvier 1990 et qui permet de déterminer l'activité antiseptique de préparations pharmaceutiques. Elle précise qu'un antiseptique doit avoir une activité telle que la concentration en microorganismes vivants d'une suspension définie de microorganismes par millilitre soit diminuée de 105 fois par contact avec celui-ci pendant une durée variant selon l'utilisation et les indications du fabricant, à une température de 32°C. La méthodologie à suivre pour cette détermination d'activité est décrite dans cette monographie ainsi qu'une liste non limitative de germes à essayer.
The antimicrobial activity of Chlorobutanol in aqueous solution at 500 mg per 100 ml was first determined. For this, two methodologies were used:
  • The methodology proposed by the European Pharmacopoeia II edition in annex VIII.14 and entitled "Efficacy of antimicrobial preservation". In this test, germ suspensions are kept in contact with the product to be evaluated for up to 28 days at 20-25 ° C. The number of cells surviving this contact is followed according to the duration of this contact. The efficiency of the conservation power is expressed in log reduction (logR) of the test germ populations. The strains to be tested are stipulated by the European Pharmacopoeia. This type of test carried out on Chlorobutanol in an aqueous solution of 500 mg per 100 ml led to the results reported in Table 1 below. Logarithmic reduction (LOG R) of microbial populations as a function of contact time with an aqueous solution of 500 mg per 100 ml of Chlorobutanol Test strains Contact time 48h 7d 14d 28d Pseudomonas acruginosa ATCC 9027 > 4.4 > 4.4 > 4.4 > 4.4 Escherichia coli ATCC 8739 > 4.3 > 4.3 > 4.3 > 4.3 Staphylococcus aureus ATCC 6538 > 4.1 > 4.1 > 4.1 > 4.1 Candida albicans ATCC 10231 > 4 > 4 > 4 > 4 Aspergillus niger ATCC 16404 0.4 1.8 2.4 2.6
  • The methodology described by the French Pharmacopoeia Xth edition in the monograph "Antiseptica" of January 1990 and which allows to determine the antiseptic activity of pharmaceutical preparations. It specifies that an antiseptic must have an activity such that the concentration of living microorganisms in a defined suspension of microorganisms per milliliter is reduced by 10 5 times by contact with it for a period varying according to the use and the indications of the manufacturer, at a temperature of 32 ° C. The methodology to be followed for this activity determination is described in this monograph as well as a non-limiting list of germs to try.

Le contact a été préalablement défini à 5 minutes sur 9 souches microbiennes (voir tableau 2 ci-après), puis a été prolongé jusqu'à 4 heures pour 5 d'entre elles (voir figure 1 annexée). Activité antiseptique du Chlorobutanol à 500 mg pour 100 ml après 5 min de contact à 32° C (exprimée en log R) P. aeruginosa A22 0,6 E coli ATCC 10536 0,3 S. aureus ATCC 9144 0 E. hirae ATCC 10541 0 S. mutans ATCC 25175 0 S. sobrinus ATCC 33478 0,5 A. actinomycetemcomitans ATCC 33384 1,3 P. intermedia NCTC 93336 1,1 C. albicans ATCC 2091 0 Contact was previously defined at 5 minutes on 9 microbial strains (see Table 2 below), then was extended up to 4 hours for 5 of them (see attached Figure 1). Antiseptic activity of Chlorobutanol 500 mg per 100 ml after 5 min of contact at 32 ° C (expressed in log R) P. aeruginosa A22 0.6 E coli ATCC 10536 0.3 S. aureus ATCC 9144 0 E. hirae ATCC 10541 0 S. mutans ATCC 25175 0 S. sobrinus ATCC 33478 0.5 A. actinomycetemcomitans ATCC 33384 1.3 P. intermedia NCTC 93336 1.1 C. albicans ATCC 2091 0

On observe que le niveau d'exigence demandé par la Pharmacopée Française n'est atteint que sur quelques souches du spectre microbien essayé.We observe that the level of requirement requested by the Pharmacopoeia French is reached only on some strains of the microbial spectrum tried.

Les bactéries gram-négatives semblent être les germes les plus sensibles. Toutefois, la durée de contact nécessaire pour obtenir les 5 logarithmes de réduction est d'environ une heure.Gram-negative bacteria seem to be the most germs sensitive. However, the contact time required to obtain the 5 log reduction is approximately one hour.

Pour les autres souches, un contact de 4 heures est toujours insuffisant. Les résultats précédents (tableau 1) obtenus sur des souches équivalentes laissent à penser que la durée de contact nécessaire serait d'au moins 2 jours.For other strains, a 4 hour contact is still insufficient. The previous results (Table 1) obtained on equivalent strains suggest that the required contact time would be at least 2 days.

En conclusion, le Chlorobutanol possède une activité antimicrobienne qui est compatible avec son utilisation à la concentration de 500 mg pour 100 ml comme agent de conservation dans les préparations pharmaceutiques. Toutefois, ces propriétés antimicrobiennes jusqu'à cette concentration et même sur des durées d'application très longues (au moins 4 heures) sont nettement insuffisantes pour revendiquer une activité antiseptique selon les termes de la Pharmacopée Française .In conclusion, Chlorobutanol has antimicrobial activity which is compatible with its use at a concentration of 500 mg for 100 ml as a preservative in preparations pharmaceutical. However, these antimicrobial properties up to this concentration and even over very long periods of application (at least 4 hours) are clearly insufficient to claim an activity antiseptic according to the terms of the French Pharmacopoeia.

L'activité antimicrobienne de la Chlorhexidine a été déterminée de la même façon.The antimicrobial activity of Chlorhexidine was determined from the same way.

On sait que l'efficacité des agents antiseptiques est liée à de nombreux paramètres : concentration initiale en actif, mode et durée d'application des produits, température de contact, nature des agents microbiens à éliminer et état physiologique de ceux-ci, présence d'agents neutralisants de l'antiseptique considéré au niveau de la zone d'application. Les concentrations en sels de Chlorhexidine dans les préparations antiseptiques peuvent ainsi varier de 50 à 4000 mg pour 100 ml selon l'usage et la présentation de ces produits (solutions pour application locale utilisées pour la préparation des champs opératoires ou l'antiseptie de peaux lésées, gels, bains de bouche, collutoires pour le traitement des affections bucco-dentaires, etc).It is known that the effectiveness of antiseptic agents is linked to many parameters: initial concentration of active ingredient, mode and duration of application of products, contact temperature, nature of microbial agents to eliminate and physiological state thereof, presence of neutralizing agents of the antiseptic considered in the area of application. The concentrations of chlorhexidine salts in preparations antiseptics can thus vary from 50 to 4000 mg per 100 ml depending on the use and presentation of these products (solutions for local application used for the preparation of surgical drapes or antiseptic damaged skin, gels, mouthwashes, mouthwashes for the treatment of oral diseases, etc.).

L'activité de la Chlorhexidine (sous la forme de ses sels) a été quantifiée en fixant les plus importants de ces paramètres. En ce qui concerne la température de contact (32°C) et le spectre microbien à essayer, les exigences de la Pharmacopée Française ont été reprises. La durée de contact a été fixée à une valeur volontairement courte (5 min) car très discriminante ; elle est aussi en relation avec l'usage thérapeuthique recherché. Les essais ont été réalisés en l'absence d'agents interférant avec l'action de la Chlorhexidine. Dans ces conditions précises de contact, on a établi les concentrations minimales nécessaires pour réduire de 105 fois la concentration en microorganismes vivants selon la définition de la Pharmacopée Française (tableau 3). Les résultats sont exprimés en Chlorhexidine base, ils sont équivalents pour chacun des sels testés (digluconate et diacétate). Concentrations minimales antiseptiques de la Chlorhexidine base (mg pour 100 ml) pour un contact de 5 min à 32° C P. aeruginosa A22 2,8 E coli ATCC 10536 1,4 S. aureus ATCC 9144 28 E. hirae ATCC 10541 280 The activity of Chlorhexidine (in the form of its salts) was quantified by fixing the most important of these parameters. With regard to the contact temperature (32 ° C) and the microbial spectrum to be tested, the requirements of the French Pharmacopoeia have been taken up. The contact time was set at a deliberately short value (5 min) because it is very discriminating; it is also related to the therapeutic use sought. The tests were carried out in the absence of agents interfering with the action of Chlorhexidine. Under these precise conditions of contact, the minimum concentrations necessary to reduce the concentration of living microorganisms by 10 5 times have been established according to the definition of the French Pharmacopoeia (Table 3). The results are expressed as Chlorhexidine base, they are equivalent for each of the salts tested (digluconate and diacetate). Minimum antiseptic concentrations of Chlorhexidine base (mg per 100 ml) for 5 min contact at 32 ° C P. aeruginosa A22 2.8 E coli ATCC 10536 1.4 S. aureus ATCC 9144 28 E. hirae ATCC 10541 280

La Chlorhexidine agit donc de manière très rapide et à faible concentration sur un large spectre bactérien. Les valeurs varient d'un germe à l'autre .Chlorhexidine therefore acts very quickly and at low concentration on a broad bacterial spectrum. Values vary from germ to another.

Pour mettre en évidence la synergie de l'activité antiseptique entre la Chlorhexidine et le Chlorobutanol, les essais réalisés précédemment ont été répétés en modifiant un seul des paramètres. Il s'agit cette fois de déterminer les concentrations minimales nécessaires en Chlorhexidine en solution, non plus dans l'eau, mais dans une solution aqueuse à 500 mg pour 100 ml de Chlorobutanol pour réduire de 105 fois la concentration en microorganismes vivants .To highlight the synergy of the antiseptic activity between Chlorhexidine and Chlorobutanol, the tests carried out previously were repeated by modifying only one of the parameters. This time it is a question of determining the minimum concentrations necessary for Chlorhexidine in solution, no longer in water, but in an aqueous solution at 500 mg per 100 ml of Chlorobutanol to reduce the concentration of living microorganisms by 10 5 times.

Les résultats ainsi obtenus ont été comparés aux résultats précédemment obtenus avec la Chlorhexidine seule (tableau 3). Le rapport entre les 2 scores a été calculé pour chaque souche, déterminant ainsi pour chaque souche microbienne un facteur de potentialisation (tableau 4). Concentrations minimales antiseptiques de la chlorhixidine base (mg/100 ml) pour un contact de 5 min à 32° C Souches testées dans l'eau (rappel tableau 3) dans le Chlorobutanol (500 mg pour 100 ml) Facteur de potentialisation P. aeruginosa A22 2,8 0,056 50 fois E. coli ATCC 10536 1,4 0,14 10 fois S. aureus ATCC 9144 28 0,28 100 fois E. hirae ATCC 10541 280 0,28 1000 fois The results thus obtained were compared with the results previously obtained with Chlorhexidine alone (Table 3). The ratio between the 2 scores was calculated for each strain, thus determining for each microbial strain a potentiating factor (Table 4). Minimum antiseptic concentrations of chlorhixidine base (mg / 100 ml) for 5 min contact at 32 ° C Strains tested in water (reminder of table 3) in Chlorobutanol (500 mg per 100 ml) Potentiation factor P. aeruginosa A22 2.8 0.056 50 times E. coli ATCC 10536 1.4 0.14 10 times S. aureus ATCC 9144 28 0.28 100 times E. hirae ATCC 10541 280 0.28 1000 times

La potentialisation de l'activité antiseptique de la Chlorhexidine par le Chlorobutanol s'exerce sur toutes les souches bactériennes testées. Elle permet de réduire considérablement (jusqu'à 1000 fois dans certains cas) les concentrations nécessaires en Chlorhexidine. Ceci est tout particulièrement vrai sur les souches gram-positives (S.aureus ATCC 9144 et E. hirae ATCC 10541) qui étaient initialement les moins sensibles à la Chlorhexidine.Potentiation of the antiseptic activity of Chlorhexidine by Chlorobutanol is exerted on all the bacterial strains tested. It allows to reduce considerably (up to 1000 times in some case) the necessary concentrations of Chlorhexidine. This is all particularly true on gram-positive strains (S. aureus ATCC 9144 and E. hirae ATCC 10541) who were initially the least sensitive with Chlorhexidine.

Des essais ont été réalisés en présence de concentrations variables de Chlorhexidine et de Chlorobutanol. Ce type d'essai a permis d'observer (tableau 5) que la quantité de Chlorobutanol permettant la potentialisation de l'activité de la Chlorhexidine est corrélée à la quantité de Chlorhexidine déjà présente dans la préparation. Ainsi donc:

  • la présence de Chlorobutanol n'est nécessaire que si la concentration de Chlorhexidine dans la préparation est insuffisante pour exprimer une activité de type antiseptique ; cette concentration limite efficace en Chlorhexidine est variable selon la souche microbienne testée comme démontré précédemment,
  • la dose à appliquer en Chlorobutanol est inversement proportionnelle à la dose de Chlorhexidine présente dans la préparation et croit rapidement vers des valeurs supérieures ou égales à 250 mg pour 100 ml ; le rapport pondéral entre la Chlorobutanol et la Chlorhexidine se situe dans un intervalle large, à partir de valeurs proches de 10 jusqu'à des valeurs supérieures à 1 000 dans certains cas. Concentration initiale en Chlorhexidine base (mg pour 100 ml) Concentration minimale en Chlorobutanol (mg pour 100 ml) qu'il faut associer pour obtenir une réduction des populations > 105 fois après 5 min de contact à 32° C et selon la souche essayée E hirae ATCC 10541 P. aeruginosa A 22 280 0 0 5,6 50 0 2,8 250 0 0,28 500 250
Tests were carried out in the presence of varying concentrations of Chlorhexidine and Chlorobutanol. This type of test made it possible to observe (Table 5) that the amount of Chlorobutanol allowing the potentiation of the activity of Chlorhexidine is correlated with the amount of Chlorhexidine already present in the preparation. Thus:
  • the presence of Chlorobutanol is only necessary if the concentration of Chlorhexidine in the preparation is insufficient to express an activity of antiseptic type; this effective limit concentration of Chlorhexidine is variable depending on the microbial strain tested as demonstrated above,
  • the dose to be applied in Chlorobutanol is inversely proportional to the dose of Chlorhexidine present in the preparation and increases rapidly to values greater than or equal to 250 mg per 100 ml; the weight ratio between Chlorobutanol and Chlorhexidine is in a wide range, from values close to 10 to values greater than 1000 in some cases. Initial concentration of Chlorhexidine base (mg per 100 ml) Minimum concentration of Chlorobutanol (mg per 100 ml) which must be combined to obtain a reduction in populations> 10 5 times after 5 min of contact at 32 ° C and depending on the strain tested E hirae ATCC 10541 P. aeruginosa A 22 280 0 0 5.6 50 0 2.8 250 0 0.28 500 250

Des essais sur différentes durées de contact montrent que la potentialisation de la Chlorhexidine par le Chlorobutanol permet de réduire le temps nécessaire à l'expression de l'activité de la Chlorhexidine. Ceci est particulièrement appréciable, par exemple, dans le cadre des bains de bouche où la durée d'application est très courte. Ceci a été démontré sur deux souches de la flore buccale : Streptococcus mutans ATCC 25175, souche cariogène (voir figure 2 annexée) et Actinobacillus actinomycetemcomitans CIP 52106 (voir figure 3 annexée), souche responsable de maladies parodontales.Tests on different contact times show that the potentiation of Chlorhexidine by Chlorobutanol allows reduce the time required to express the activity of the Chlorhexidine. This is particularly appreciable, for example, in mouthwashes where the duration of application is very short. This has been demonstrated on two strains of the oral flora: Streptococcus mutans ATCC 25175, cariogenic strain (see attached Figure 2) and Actinobacillus actinomycetemcomitans CIP 52106 (see Figure 3 attached), strain responsible for periodontal diseases.

Ainsi, l'association Chlorhexidine - Chlorobutanol permet d'obtenir un pouvoir antiseptique en 1 min équivalent (cas de S. mutans), voire supérieur (cas d'A. actinomycetemcomitans) à celui obtenu après 5 min.de contact avec la Chlorhexidine seule. Ceci est particulièrement vrai dans le cas où les doses appliquées en Chlorhexidine sont très faibles (inférieures à 5,6 mg pour 100 ml). Dans les mêmes conditions de contact le Chlorobutanol seul n'exerce pas ou peu d'activité. En effet, en présence de 500 mg pour 100 ml de Chlorobutanol, le logarithme de réduction des populations de S. mutans est nul après 5 min de contact à 32° C (figure 2 annexée) et de 1,3 pour A. actinomycetemcomitans (figure 3 annexée).Thus, the combination Chlorhexidine - Chlorobutanol allows to obtain an antiseptic power in 1 min equivalent (case of S. mutans), even higher (case of A. actinomycetemcomitans) than that obtained after 5 min. of contact with Chlorhexidine alone. This is particularly true in case the doses applied in Chlorhexidine are very low (less than 5.6 mg per 100 ml). Under the same conditions of contact Chlorobutanol alone has little or no activity. Indeed, in presence of 500 mg per 100 ml of Chlorobutanol, the logarithm of reduction in S. mutans populations is zero after 5 min of contact at 32 ° C (Figure 2 attached) and 1.3 for A. actinomycetemcomitans (Figure 3 attached).

On se trouve donc bien en présence d'une potentialisation et non pas d'une additivité d'activité .So we are in the presence of a potentiation and not activity additivity.

En conclusion, après avoir mis en évidence l'absence de propriétés antiseptiques de la part du Chlorobutanol et les limites de l'activité antiseptique de la Chlorhexidine, la présente invention démontre que l'ajout de Chlorobutanol dans des préparations à base de Chlorhexidine ou de ses sels permet d'augmenter de manière importante l'activité de cet antiseptique. La' potentialisation se traduit par une diminution de la concentration utile en Chlorhexidine et / ou une diminution du temps de contact utile à son action. Cette potentialisation s'exprime aussi par le fait que, pour une concentration donnée, le spectre d'activité de la Chlorhexidine est élargi grace à l'augmentation de la sensibilité des germes à cet antiseptique .In conclusion, after having highlighted the absence of properties antiseptics from Chlorobutanol and activity limits Chlorhexidine antiseptic, the present invention demonstrates that the addition of Chlorobutanol in preparations based on Chlorhexidine or its salts can significantly increase the activity of this antiseptic. Potentiation results in a decrease in useful concentration of Chlorhexidine and / or a reduction in the time useful contact for its action. This potentialization is also expressed by the fact that, for a given concentration, the spectrum of activity of the Chlorhexidine is enlarged thanks to the increased sensitivity of germs to this antiseptic.

Cette potentialisation permet la formulation de préparations antiseptiques très faiblement dosées en Chlorhexidine (par exemple : entre 0,5 et 25 mg pour 100 ml de Digluconate de Chlorhexidine) et contenant du Chlorobutanol (par exemple: de 200 à 500 mg pour 100 ml de Chlorobutanol hémi-hydraté) . Ces préparations sont efficaces même avec des durées de contact très courtes (de l'ordre de 1 min). Le rapport pondéral optimum Chlorobutanol/Chlorhexidine base est compris entre 14 et 1800. Cette base active est transposable à toutes les formes galéniques : liquides, pâteuses, ou solides.This potentiation allows the formulation of preparations antiseptics very low in Chlorhexidine (for example: between 0.5 and 25 mg per 100 ml of Chlorhexidine Digluconate) and containing Chlorobutanol (for example: 200 to 500 mg per 100 ml Chlorobutanol hemihydrate). These preparations are effective even with very short contact times (around 1 min). The report Chlorobutanol / Chlorhexidine base optimum weight is between 14 and 1800. This active base can be transposed to all forms galenical: liquid, pasty, or solid.

La présente invention offre de nombreux avantages :

  • Elle permet, par l'ajout de Chlorobutanol, de renforcer l'activité antimicrobienne de compositions pharmaceutiques à base de Chlorhexidine (ou de ses sels hydrochloriques, acétiques, gluconiques, etc). Ceci est particulièrement appréciable pour les produits dont les temps d'application sont obligatoirement courts (bains de bouches, produits à rincer, etc), pour les compositions contenants des substances peu compatibles avec la Chlorhexidine et ses sels (tensio-actifs anioniques, surfactifs non ioniques, etc) ou lorsque l'activité des compositions doit s'exercer en présence d'agents interférants (protéines, phospholipides, etc).
  • Elle permet, en diminuant la concentration en Chlorhexidine ou ses sels, de réduire leurs effets secondaires (coloration de la langue et des dents, irritations cutanées, eczémas allergiques, photosensibilisation, etc).
  • Elle permet l'élargissement du spectre d'activité des compositions pharmaceutiques associant ces deux agents antimicrobiens.
The present invention offers many advantages:
  • It allows, by the addition of Chlorobutanol, to reinforce the antimicrobial activity of pharmaceutical compositions based on Chlorhexidine (or its hydrochloric, acetic, gluconic salts, etc.). This is particularly appreciable for products whose application times are necessarily short (mouthwashes, rinsing products, etc.), for compositions containing substances that are not very compatible with Chlorhexidine and its salts (anionic surfactants, non-surfactants ionic, etc.) or when the activity of the compositions must be exercised in the presence of interfering agents (proteins, phospholipids, etc.).
  • It makes it possible, by reducing the concentration of Chlorhexidine or its salts, to reduce their side effects (coloring of the tongue and teeth, skin irritations, allergic eczema, photosensitization, etc.).
  • It allows the broadening of the spectrum of activity of pharmaceutical compositions combining these two antimicrobial agents.

Bien entendu, la présente invention est applicable à un grand nombre de formes pharmaceutiques antiseptiques telles que :

  • solutions
  • solutions moussantes
  • émulsions ou pommades
  • gels
  • savons
  • sticks
  • bains de bouches et collutoires
  • pâtes dentifrices
  • comprimés
  • comprimés hydro-dispersibles
  • tablettes / comprimés à sucer ou à croquer
  • sprays
  • shampooing
Of course, the present invention is applicable to a large number of antiseptic pharmaceutical forms such as:
  • solutions
  • foaming solutions
  • emulsions or ointments
  • gels
  • soaps
  • sticks
  • mouthwashes and mouthwashes
  • toothpaste
  • tablets
  • water dispersible tablets
  • lozenges / chewable tablets
  • sprays
  • shampoo

A titre d'illustration, on mentionnera quelques exemples de formes pharmaceutiques : Exemple de solution antiseptique pour 100 ml : Digluconate de Chlorhexidine de 0,5 à 25 mg Chlorobutanol hémihydraté de 200 à 500 mg Parfum de 0,05 à 3 ml Eau purifiée qsp 100 ml Exemple de bain de bouche pour 100 ml : Digluconate de Chlorhexidine de 0,5 à 25 mg Chlorobutanol hémihydraté de 200 à 500 mg Alcool éthylique à 95% de 1 à 30 ml Aromes exemples : - Menthol de 50 mg à 150 mg - Solution alcoolique d'essence de Menthe de 0,5 à 2 ml Eau purifiée qsp 100 ml Exemple de crème antibactérienne pour 100 ml : Diacétate de Chlorhexidine de 0,35 à 17,5 mg Chlorobutanol hémihydraté de 200 à 500 mg Huile de Vaseline épaisse de 1 à 20 g Cire émulsionnante à base d'alcool gras de 1 à 20 g Antioxydant de 10 à 500 mg Eau purifiée qsp 100 ml By way of illustration, a few examples of pharmaceutical forms will be mentioned: Example of antiseptic solution for 100 ml: Chlorhexidine digluconate 0.5 to 25 mg Chlorobutanol hemihydrate 200 to 500 mg Perfume from 0.05 to 3 ml Purified water qs 100 ml Mouthwash example for 100 ml: Chlorhexidine digluconate 0.5 to 25 mg Chlorobutanol hemihydrate 200 to 500 mg 95% ethyl alcohol from 1 to 30 ml Sample flavors: - Menthol from 50 mg to 150 mg - Alcoholic mint essence solution 0.5 to 2 ml Purified water qs 100 ml Example of antibacterial cream for 100 ml: Chlorhexidine diacetate 0.35 to 17.5 mg Chlorobutanol hemihydrate 200 to 500 mg Thick Vaseline Oil from 1 to 20 g Emulsifying wax based on fatty alcohol from 1 to 20 g Antioxidant from 10 to 500 mg Purified water qs 100 ml

Claims (8)

  1. Antiseptic composition, in particular a topical pharmaceutical preparation based on a combination of chlorobutanol in anhydrous or hemihydrate form with chlorhexidine or one of its salts, characterized in that:
    the chlorobutanol is present at a minimum concentration of about 200 mg per 100 ml,
    the chlorhexidine or its salt is present at a concentration, expressed as chlorhexidine base, of 0.28 mg to 14 mg per 100 ml, and
    the weight ratio between the chlorobutanol and chlorhexidine, expressed as a free base, is between 14 and 1 800.
  2. Composition according to Claim 1, characterized in that the chlorobutanol is present at a concentration of about 500 mg per 100 ml.
  3. Composition according to either of Claims 1 and 2, characterized in that the chlorhexidine salt is chosen from its acetic, hydrochloric and gluconic salts.
  4. Composition according to one of Claims 1 to 3, characterized in that the chlorobutanol is used in the form of its hemihydrate.
  5. Composition according to one of Claims 1 to 4, characterized in that the chlorhexidine or its salt is present at a concentration, expressed as a free base, of 0.28 mg to 1.4 mg per 100 ml, conferring a bactericidal effect on the said composition.
  6. Composition according to one of Claims 1 to 4, characterized in that the chlorhexidine or its salt is present at a concentration, expressed as a free base, of 1.4 mg to 14 mg per 100 ml, conferring bactericidal and fungicidal effects on the said composition.
  7. Composition according to one of Claims 1 to 6, characterized in that it comprises per 100 ml:
    chlorhexidine digluconate: from 0.5 to 25 mg,
    chlorobutanol: from 200 to 500 mg.
  8. Composition according to one of Claims 1 to 6, characterized in that it comprises per 100 ml:
    chlorhexidine diacetate: from 0.35 to 17.5 mg,
    chlorobutanol: from 200 to 500 mg.
EP97907152A 1996-03-04 1997-02-28 Antiseptic compositions containing chlorobutanol and chlorhexidine Expired - Lifetime EP0884948B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9602685 1996-03-04
FR9602685A FR2745499B1 (en) 1996-03-04 1996-03-04 ANTISEPTIC COMPOSITIONS BASED ON CHLOROBUTANOL AND CHLORHEXIDINE
PCT/FR1997/000362 WO1997032479A1 (en) 1996-03-04 1997-02-28 Antiseptic compositions containing chlorobutanol and chlorhexidine

Publications (2)

Publication Number Publication Date
EP0884948A1 EP0884948A1 (en) 1998-12-23
EP0884948B1 true EP0884948B1 (en) 2001-12-19

Family

ID=9489818

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97907152A Expired - Lifetime EP0884948B1 (en) 1996-03-04 1997-02-28 Antiseptic compositions containing chlorobutanol and chlorhexidine

Country Status (6)

Country Link
EP (1) EP0884948B1 (en)
DE (1) DE69709317T2 (en)
ES (1) ES2169358T3 (en)
FR (1) FR2745499B1 (en)
PT (1) PT884948E (en)
WO (1) WO1997032479A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2972347A1 (en) * 2011-03-11 2012-09-14 Pf Medicament COMPOSITION FOR CARE AND / OR ORAL HYGIENE

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE533425C2 (en) * 2008-07-07 2010-09-21 Ambria Dermatology Ab Antimicrobial composition
FR3065879B1 (en) 2017-05-02 2020-11-20 Pf Medicament ANTISEPTIC COMPOSITION OF A COMBINATION OF CHLORHEXIDINE AND IODINE

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2972347A1 (en) * 2011-03-11 2012-09-14 Pf Medicament COMPOSITION FOR CARE AND / OR ORAL HYGIENE
WO2012123383A3 (en) * 2011-03-11 2013-01-03 Pierre Fabre Medicament Buccodental hygiene and/or care composition

Also Published As

Publication number Publication date
DE69709317T2 (en) 2002-08-14
WO1997032479A1 (en) 1997-09-12
ES2169358T3 (en) 2002-07-01
DE69709317D1 (en) 2002-01-31
FR2745499A1 (en) 1997-09-05
PT884948E (en) 2002-06-28
FR2745499B1 (en) 1998-05-22
EP0884948A1 (en) 1998-12-23

Similar Documents

Publication Publication Date Title
KR20150097560A (en) Botanical antimicrobial compositions
WO2007092811A2 (en) Sialagogue based oral care products
FR2552305A1 (en) HIGH BACTERICIDAL COMPOSITION CONTAINING BIGUANIDE AND PYRIMIDINE
EP0904054B1 (en) USE OF alpha-ALKYLGLUCOSIDES AND alpha-ALKYLGLUCOSIDE ESTERS AS ANTI-MICROBIAL EMULSIFYING AGENTS
FR2729050A1 (en) Synergistic compsn. with microbicidal properties
EP2200582B1 (en) Use of carriers as preservatives and pharmaceutical composition containing same
EP0884948B1 (en) Antiseptic compositions containing chlorobutanol and chlorhexidine
FR2855721A1 (en) Antiseptic microbicide useful as a preservative in cosmetic, pharmaceutical or food products comprises 1,2-alkanediols and glycerol fatty acid monoester derivatives
FR2932386A1 (en) Composition, comprises at least three original natural bioactive compounds e.g. Aloe vera, apricot kernel, rosehip and manuka, with additional ingredients e.g. zinc, iron and phosphorus
FR2857222A1 (en) Microbicidal antiseptic, useful in cosmetics, pharmaceuticals and foods, is a synergistic mixture of 1,2-alkanediol and tea tree oil
FR2714603A1 (en) Dermatological composition and its use for the preparation of a medicament
EP0869800B1 (en) Acylglycine- and zinc salt-based antibacterial compound
FR2972347A1 (en) COMPOSITION FOR CARE AND / OR ORAL HYGIENE
EP0465313B1 (en) Healing composition for local application
JP2010195706A (en) New germicidal, fungicidal and moisturizing composition
US20130034618A1 (en) Compositions for treating the integument
FR2902290A1 (en) Novel bacteriostatic preservative agent, useful e.g. in gels, emulsions, lotions, creams, ointments, sun screen products and veterinary products, comprises combination of salicylic acid and Lonicera japonica extract in an aqueous vehicle
EP1247521B1 (en) Use of biguanide and pyrimidine derivatives for the preparation of a topical skin care composition
RU2786973C1 (en) Antibacterial hand treatment
WO2018202687A1 (en) Antiseptic composition combining chlorhexidine and iodine
JP2023529899A (en) Eco-biological lipo-alcoholic composition
JP2012224609A (en) Novel antibacterial, antifungal, moisturizing and anti-inflammatory agent causing no skin irritation
FR2851161A1 (en) Use of antimicrobial mixture comprising sebacic acid, 10-hydroxydecanoic acid and 1,10-decanediol for treating skin and hair
WO2005107696A1 (en) Cosmetic and/or dermatological composition exhibiting preservative hypoallergenic properties
FR2902291A1 (en) Novel bacteriostatic preservative agent, useful e.g. in gels, emulsions, lotions, creams, ointments, milk, masks, sun screen and veterinary products, comprises combination of salicylic acid and Lonicera japonica extract in aqueous vehicle

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19980928

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): CH DE ES GB IT LI LU MC PT

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

17Q First examination report despatched

Effective date: 20010521

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): CH DE ES GB IT LI LU MC PT

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: GB

Ref legal event code: IF02

REF Corresponds to:

Ref document number: 69709317

Country of ref document: DE

Date of ref document: 20020131

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: MICHELI & CIE INGENIEURS-CONSEILS

GBT Gb: translation of ep patent filed (gb section 77(6)(a)/1977)

Effective date: 20020319

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20020308

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2169358

Country of ref document: ES

Kind code of ref document: T3

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20160121

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20160301

Year of fee payment: 20

Ref country code: IT

Payment date: 20160212

Year of fee payment: 20

Ref country code: CH

Payment date: 20160208

Year of fee payment: 20

Ref country code: MC

Payment date: 20160118

Year of fee payment: 20

Ref country code: DE

Payment date: 20160212

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20160216

Year of fee payment: 20

Ref country code: PT

Payment date: 20160118

Year of fee payment: 20

REG Reference to a national code

Ref country code: DE

Ref legal event code: R071

Ref document number: 69709317

Country of ref document: DE

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: GB

Ref legal event code: PE20

Expiry date: 20170227

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20170227

Ref country code: PT

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20170308

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20170626

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20170301